Elevated depressive symptoms in smokers has reliably been associated with smoking cessation failure. While several antidepressant medications have demonstrated efficacy for smoking cessation, fluoxetine has specifically shown promise in the treatment of smokers with elevated levels of depressive symptoms. We recently completed a randomized clinical trial of fluoxetine for smokers with elevated depressive symptoms, and found that sequential use of fluoxetine (starting 8 weeks prior to quit date) resulted in superior smoking cessation outcomes compared to concurrent use of fluoxetine. However, one limitation of our prior study design is that we could not rule out the possibility that our findings may have been due to placebo effects or the effects of additional contact time. Therefore, before disseminating this approach in clinical practice settings, we believe that it is critical to first determine whether this is an active pharmacologic effect of fluoxetine. The proposed study is a randomized, double-blind, placebo controlled trial of fluoxetine, used sequentially as in our earlier study. This trial is intended to test the primary hypothesis that among 206 smokers with elevated depressive symptoms (CESD >6), sequential antidepressant pharmacotherapy with (20 mg.) fluoxetine (FLUOXSEQ), begun 8 weeks prior to and extended throughout brief standard smoking cessation treatment with transdermal nicotine patch (ST-TNP), will result in superior smoking cessation outcomes compared to sequential pharmacotherapy with placebo medication (PLAC-SEQ) combined with ST-TNP, according to the identical treatment schedule. Smoking outcomes will be assessed throughout treatment and at 2-, 6- and 12-month follow-ups. Current and past psychiatric diagnoses will be assessed, as will changes in depressive symptoms, nicotine withdrawal symptoms and associated mood states.